Most human protein therapeutics require frequent dosing due to rapid clearance of the proteins from the body. Development of second generation protein pharmaceuticals that can be injected less frequently is of considerable interest to patients and healthcare providers. We propose to create long-acting forms for growth hormone, granulocyte colony stimulating factor and erythropoietin by creating larger forms of these proteins with longer circulating half-lives. We believe these modified proteins will possess biological activities equal or superior to the corresponding natural proteins in vivo, but will require less frequent dosing, on the order of once every two to four weeks, rather than daily or every other day. During Phase I we will construct the modified proteins and demonstrate that they possess at least wild type in vitro bioactivities. During phase II, we will manufacture sufficient quantities of the modified proteins for testing in animal disease models. The improved characteristics of the novel proteins will reduce the amount of protein required per patient, improve patient compliance and quality of life and result in considerable cost savings to patients and healthcare providers. These proteins will find utility in treating endocrine and hematopoietic disorders, and complications of AIDS and cancer chemotherapy. PROPOSED COMMERCIAL APPLICATION: The long-acting forms of human growth hormone, G-CSF and EPO under development will be used to treat short stature, cachexia, neutropenia and anemia. Long-acting forms of these proteins will require much less frequent dosing than existing products, providing significant cost savings to patients and healthcare providers. Additional potential benefits include improved drug efficacy and improved patient quality of life.